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Breast Cancer and Benign Breast Disorders
Breast Cancer
Epidemiology and Pathobiology
Invasive breast cancer, which is the most common nonskin cancer in women in the United States, is diagnosed in approximately 290,000 women annually and results in approximately 43,000 deaths each year. Worldwide, about 2.25 million cases are diagnosed annually. The incidence and mortality from breast cancer appear to be declining in the United States and parts of Western Europe, likely because of a decreased use of postmenopausal hormone replacement therapy ( Chapter 222 ), early detection by screening mammography, and widespread use of adjuvant systemic therapy.
Breast cancer is largely a disease of women, but it occurs in men at an incidence of approximately 1% of the incidence seen in women. A second critical risk factor is age. Approximately 75% of breast cancer cases in the United States are diagnosed in women older than age 50 years.
Family history is a third critical risk factor ( Table 183-1 ). Approximately 20% of breast cancers occur in women with a family history of breast cancer, and a diagnosis of breast cancer in first-degree relatives before age 50 years especially increases the risk. Of breast cancer cases, 5 to 8% occur in high-risk families. Familial breast cancer syndromes that are associated with known molecular abnormalities include the breast-ovarian cancer syndrome, which is linked to germline mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2 . These mutations, which include specific breast cancer cluster regions within these genes, are inherited in an autosomal dominant fashion. Germline mutation in either of these BRCA genes is associated with a 50 to 85% lifetime risk for developing breast cancer.
TABLE 183-1
RISK FACTORS FOR BREAST CANCER IN WOMEN
Modified from American Cancer Society. Breast Cancer Facts & Figures 2017-2018 . ACS; Atlanta, GA: 2017; Hu C, Hart SN, Gnanaolivu R, et al. A population-based study of genes previously implicated in breast cancer. N Engl J Med . 2021;384:440-451.
| RELATIVE RISK >4.0 |
| Age (65+ vs. <65 yr, although risk increases across all ages until age 80 yr) Biopsy-confirmed atypical hyperplasia Certain inherited genetic mutations for breast cancer, including BRCA1, BRCA2, p53, CHEK2, PALB2, PTEN Ductal carcinoma in situ Lobular carcinoma in situ Mammographically dense breasts (compared with least dense) Personal history of early-onset (<40 yr) breast cancer Two or more first-degree relatives with breast cancer diagnosed at an early age |
| RELATIVE RISK 2.1-4.0 |
| Personal history of breast cancer (40+ yr) High endogenous estrogen or testosterone levels (postmenopausal) High-dose radiation to chest One first-degree relative with breast cancer |
| RELATIVE RISK 1.1-2.0 |
| Alcohol consumption Ashkenazi Jewish heritage Diethylstilbestrol exposure Early menarche (<12 yr) Height (tall) High socioeconomic status Late age at first full-term pregnancy (>30 yr) Late menopause (>55 yr) Never breastfed a child No full-term pregnancies Obesity (postmenopausal)/adult weight gain Personal history of endometrial or ovarian cancer Proliferative breast disease without atypia (usual ductal hyperplasia and fibroadenoma) Recent and long-term use of menopausal hormone therapy containing estrogen and progestin Recent oral contraceptive use |
Other hereditary cancer syndromes ( Chapter 166 ) include the Li-Fraumeni syndrome (which is linked with germline mutations in the p53 tumor suppressor gene), Cowden syndrome (which is associated with inherited mutations in the PTEN gene), and germline loss-of-function mutations in PALB2, CHEK2 , and other DNA repair genes. In addition to these high-penetrance genetic susceptibility syndromes, low-penetrance genetic associations include single nucleotide polymorphisms in a variety of genes.
Reproductive risk factors that result in prolonged exposure of the breast to estrogen include early menarche, late menopause, nulliparity, and late first pregnancy. The association between postmenopausal obesity and breast cancer likely reflects estrogen exposure as well.
Certain types of preexisting breast pathology, including atypical hyperplasia and lobular carcinoma in situ, are also associated with increased risk of breast cancer. Breast density as assessed by mammography may also be a risk factor.
Exogenous environmental factors that may predispose to breast cancer include ionizing radiation during adolescence, prolonged use of combined estrogen plus progesterone hormone replacement therapy (but not estrogen therapy alone), ongoing use of oral contraceptives, and alcohol consumption. Large studies have failed to show any convincing association between breast cancer and exposure to estrogenic pesticides or to a high-fat diet.
Clinical Manifestations
Breast cancer usually manifests as an asymptomatic abnormality on a screening mammogram. However, patients sometimes have a physical change in the breast, including a mass or asymmetrical thickening, nipple discharge, or skin or nipple changes. These abnormalities are commonly first detected by the patient but also may first be noted on a routine physical examination by a clinician.
A milky discharge is seldom associated with a malignant diagnosis, but a clear or bloody nipple discharge is of great concern, and a bloody discharge is frequently caused by an intraductal papilloma. Breast pain is common, especially as a premenstrual symptom in premenopausal women, but it may also be associated with an underlying malignancy.
Paget disease of the nipple is a form of adenocarcinoma that involves the skin and ducts and is manifested as nipple excoriation. Inflammatory breast cancer is characterized by a constellation of redness, warmth, and edema that often reflects infiltration of tumor cells into the dermal lymphatics of the breast, and can mimic simple mastitis.
Although most breast cancers are localized or relatively localized at the time of diagnosis, metastatic disease can be seen at the time of presentation or up to decades later. Common metastatic sites include bone, with pain and pathologic fractures ( Chapter 187 ); liver metastases, with elevations of liver enzymes and sometimes jaundice; pleura, with malignant effusions ( Chapter 86 ); central nervous system, with space occupying lesions and spinal cord compression ( Chapter 175 ); and pericardium, with effusions ( Chapter 62 ). Breast cancer is also a common cause of a hypercoagulable state ( Chapter 67 ) manifested by deep vein thrombosis of the legs and even thromboses of the upper extremity ( Chapter 68 ).
Diagnosis
Patients who have an asymptomatic mammographic abnormality or any of the clinical manifestations associated with breast cancer, whether initially noted by the patient or by an examining clinician, require a careful history and breast examination, including palpation for potentially suspicious axillary lymph nodes. A careful history should focus on family history and exposure to estrogens and hormone replacement therapy. The physical examination should include inspection of the breasts for changes in shape, skin color, or dimpling with the patient’s hands above their head and on the hips; palpation of the breasts in the upright and reclining positions using a standard approach of circles, wedges, or lines to cover the entire breast; and examination of the axillary, supraclavicular, and infraclavicular lymph nodes. If the abnormality was not detected by a screening mammogram, a mammogram should be obtained promptly.
If the breast examination and bilateral mammography are normal in patients who have localized noncyclic breast pain, ultrasound or magnetic resonance imaging (MRI) may be used to exclude the small possibility of a malignancy. Bilateral breast imaging is always recommended to identify any unsuspected lesions in the contralateral breast that may also require evaluation.
For both clinically occult and clinically apparent lesions, pathologic evaluation is mandatory to establish a diagnosis. An outpatient core needle biopsy should be guided by mammography, ultrasonography, or MRI if the lesion is not palpable. In patients who have clear or bloody nipple discharge, ductography and ductoscopy may help to identify the inciting lesion, but excisional biopsy may be required.
These technologies generally permit an accurate diagnosis that can be followed by definitive treatment, but the concordance among pathologists is only about 96% for the diagnosis of invasive carcinoma, about 85% for ductal carcinoma in situ or fully benign biopsies, and as low as 50% for atypia. Further expert evaluation is required when biopsy of a suspicious lesion yields equivocal diagnosis after needle aspiration or core biopsy.
Staging and Prognostic and Predictive Markers
Breast cancers are staged from I to IV, with stages I and II representing early-stage disease, stage III signaling more locally advanced disease, and stage IV denoting metastatic disease. Outcomes are highly correlated with stage of disease.
Anatomic staging ( Table 183-2 ) considers just the tumor’s size (T), nodal involvement (N), and metastases (M) and should only be used in global regions where biomarker tests are not routinely available. Most patients with breast cancer present with anatomic stage I or II disease in the absence of symptoms. In such patients, basic laboratory studies can be limited to blood counts, chemistry panel, and a chest radiograph, because more extensive radiologic evaluation is not warranted because of low yield. In contrast, women with clinical evidence of stage III or IV disease should undergo more intensive evaluation of common sites for metastases, including lung, liver, and bone, using computed tomography (CT) and positron emission tomographic (PET) radionuclide scanning.
TABLE 183-2
ANATOMIC STAGING OF BREAST CANCER
| STAGE | DESCRIPTION |
|---|---|
| NONINVASIVE | |
| 0 |
|
| INVASIVE | |
| 1A |
|
| 1B |
|
| IIA |
|
| IIB |
|
| IIIA |
|
| IIIB |
|
| IIIC |
|
| METASTATIC | |
| IV |
|
However, all patients with invasive cancers (anatomic stage 1 A or higher) also should undergo pathological prognostic staging, which incorporates a number of biomarkers (including histologic grade, expression of estrogen and progesterone receptors and HER2 proteins, and sometimes multigene panels). By integrating data derived from analysis by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing, and reverse-phase protein arrays, breast cancers can be divided into at least four molecular subsets: luminal A and B, HER2, and basal. The luminal subtypes frequently express the estrogen receptor-α, but luminal A appears to be associated with a better prognosis and higher likelihood of response to endocrine therapy than luminal B. The basal subtype is dominated by tumors that lack expression of the estrogen receptor-α, the progesterone receptor, or HER2—the so-called triple-negative breast cancer that lacks a readily identified molecular target. Multigene assays can identify early-stage steroid receptor–positive breast cancers that will benefit from the addition of chemotherapy to endocrine therapy and may identify women with a poor prognosis. Whole-genome sequencing of the breast cancer also may help to pinpoint avenues for precise diagnostics and targeted therapy.
Germline testing for BRCA1 and BRCA2 mutations through a multigene panel should be part of the evaluation of women with clinical features suggestive of a hereditary breast cancer syndrome (e.g., a personal diagnosis of breast cancer at age 45 years or younger or of ovarian cancer at any age, a personal diagnosis of triple-negative breast cancer at age 60 years or younger, multiple family members with early-onset breast or ovarian cancer, bilateral breast cancer, or Ashkenazi Jewish heritage). Careful counseling about the implications of positive or negative results and about the limitations of testing is a prerequisite for testing.
Less than 10% of women present initially with metastatic disease. Advanced disease is more commonly diagnosed in women who have a previous diagnosis of early breast cancer for which they have received treatment. Common sites for metastases include bone, soft tissues, lung, liver, and brain. If metastatic disease is suspected, relevant hematologic, biochemical, and radiographic evaluation is indicated to assess the location and severity of involvement. Because of the importance of the diagnosis, pathologic confirmation is preferred to verify recurrent disease, exclude other diagnoses, and reassess of biologic features such as the expression of estrogen receptors, progesterone receptors, and HER2. Elevation of tumor markers (e.g., CA-27-29, carcinoembryonic antigen) or the presence of circulating tumor cells or circulating free tumor DNA is not diagnostic of recurrent disease, although these markers may be useful adjuncts in the assessment of the effects of therapy.
Treatment
The treatment of breast cancer should be tailored to its stage and biology. For example, tumors that express the estrogen receptor-α, the progesterone receptor, or both, are responsive to endocrine therapy, whereas tumors that lack both seldom respond to such therapy. Overexpression of the HER2 protein is associated with response to the HER2-targeted therapies. Evidence that links expression of the estrogen receptor, the progesterone receptor, or HER2 to the efficacy of chemotherapy is equivocal.
In Situ Carcinoma
In countries where screening mammography is widely used, in situ carcinomas account for 20 to 25% of newly diagnosed cases of breast cancer (see Table 183-3 ).
TABLE 183-3
CARCINOMA IN SITU: DUCTAL VERSUS LOBULAR
| FEATURE | LOBULAR CARCINOMA IN SITU | DUCTAL CARCINOMA IN SITU |
|---|---|---|
| Age | Younger | Older |
| Palpable mass | No | Uncommon |
| Mammographic appearance | Not detected on mammography | Microcalcifications, mass |
| Immunophenotype | E-cadherin negative | E-cadherin positive |
| Usual manifestation | Incidental finding on breast biopsy | Microcalcifications on mammography or breast mass |
| Bilateral involvement | Common | Uncertain |
| Risk and site of subsequent breast cancer | 25% risk for invasive breast cancer in either breast over remaining lifespan | At site of initial lesion; 0.5% risk/yr of invasive breast cancer in opposite breast |
| Prevention | Consider tamoxifen or raloxifene or aromatase inhibitor | Consider tamoxifen or aromatase inhibitor if estrogen receptor positive |
| Treatment | Yearly mammography and breast examination | Lumpectomy ± radiation; mastectomy for large or multifocal lesions |
Ductal Carcinoma In-Situ
Most in situ breast tumors are ductal carcinoma in situ (DCIS) lesions, which are associated with approximately a 30% risk for the development of subsequent invasive breast cancer in the same breast. The risk for metastatic breast cancer with a diagnosis of DCIS is extremely small. As a consequence, management decisions are centered on the involved breast, and axillary lymph node evaluation is not routinely performed. Total mastectomy has a high likelihood of cure, but lumpectomy with conservation of the breast is appropriate for many women with DCIS. Sufficient excision to obtain tumor-free margins is critical. Careful examination of the specimen and postexcision mammography are crucial to confirm that the DCIS has been adequately excised. The size and grade of the lesion are other important determinants of local outcome.
Radiotherapy plus lumpectomy decreases the likelihood of in situ or invasive recurrence compared with lumpectomy alone, but women who have favorable histologic findings and who are willing to undergo close surveillance are candidates for local excision alone. In addition, the use of oral tamoxifen (20 mg daily) or an aromatase inhibitor (e.g., oral anastrozole 1 mg daily) for 5 years can reduce the likelihood of recurrent ipsilateral breast cancer or a new contralateral breast cancer by approximately 50%.
Lobular Carcinoma In Situ
Controversy continues over whether lobular carcinoma in situ (LCIS) is truly a malignant lesion. LCIS is usually an incidental finding on a breast biopsy that was performed for other indications, and it appears to be associated with a 25% risk for the development of invasive breast cancer in either breast. Women with LCIS are generally managed expectantly with regular breast examination and imaging. Bilateral total mastectomy is sometimes considered for women whose LCIS is associated with other risk factors for breast cancer or with extreme anxiety. Women with LCIS are candidates for tamoxifen (20 mg daily), raloxifene (60 mg daily), or an aromatase inhibitor (e.g., anastrozole 1 mg daily) as a risk-reduction strategy.
Early Stage Invasive Breast Cancer
Surgery
Breast conservation surgery with lumpectomy plus radiotherapy provides identical survival rates to modified radical mastectomy (removal of the breast and lymph nodes) for women with stages I and II breast cancer. Medical contraindications to breast conservation therapy include multifocal disease, previous radiotherapy, ongoing pregnancy that precludes the timely use of radiotherapy, poor cosmesis, and patient preference. Patients who undergo mastectomy should be counseled about the availability of autologous tissue and implant options for reconstruction, either at the time of surgery or any time thereafter.
For women who have small tumors and a clinically negative axilla, including on axillary node ultrasonography, no further local evaluation is needed. For adequate staging of larger tumors, however, the involvement of axillary lymph nodes must be determined. To minimize the incidence of postoperative lymphedema associated with lymph node dissection, a radioactive tracer, blue dye, or both are injected into the area around the primary breast tumor and tracked to the dominant axillary lymph node (the sentinel node), which can be located and removed by the surgeon. If the sentinel node is tumor free or if the burden of disease in sentinel nodes is low, no further axillary surgery is required. Women who have palpable axillary nodes or who have extensively involved sentinel nodes should be counseled to undergo axillary dissection.
Adjuvant Radiotherapy
Women who have undergone lumpectomy alone have a breast cancer recurrence rate of up to 40%, whereas the rate of recurrence is less than 10% with whole-breast radiotherapy, often administered on an accelerated schedule. Women who are older than age 65 years and who receive tamoxifen for low-risk estrogen receptor–positive tumors will have a lower rate of local recurrence but no benefit in terms of distant recurrence or survival. In women who have positive axillary nodes or high-risk characteristics despite negative nodes, radiation therapy appears to reduce recurrence rates and breast cancer mortality, with a smaller overall survival benefit.
Women who have undergone mastectomy also likely gain a survival advantage from postoperative radiation therapy if they have more than three involved lymph nodes. For women who have involvement of one to three nodes, the potential benefit is smaller, and expert consultation is helpful.
Adjuvant Systemic Therapy
Neoadjuvant Chemotherapy
Women frequently receive several adjuvant interventions, including chemotherapy, radiotherapy, endocrine therapy, and/or anti-HER2 therapy. For clinically node-positive tumors or tumors larger than 2 cm, neoadjuvant preoperative checkpoint inhibitor therapy with pembrolizumab plus chemotherapy is standard treatment for triple-negative breast cancer, and neoadjuvant anti-HER2 therapy plus chemotherapy should be considered for HER2-positive breast cancer. Otherwise, neoadjuvant chemotherapy improves the rate of breast conservation but does not enhance disease-free or overall survival.
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